Role of Neuronal Mitochondrial Metabolic Phenotype in Pathogenesis of ALS

Panov, Alexander; Steuerwald, Nury; Вавилин, В. А.; Dambinova, Svetlana A.; Bonkovsky, Herbert L.

doi:10.5772/30418

Cited by 5 publications

(14 citation statements)

References 98 publications

(221 reference statements)

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“…Although some researchers accept that the neuromediators glutamate [ 60 ] and GABA [ 61 ] may undergo oxidative degradation both in neurons and astroglia, there was little evidence obtained at the mitochondrial level. We have recently presented the evidence that isolated brain and spinal cord mitochondria require amino acid glutamate for the maximal rates of oxidative phosphorylation [ 10 , 62 ]. Thus the energy metabolism of the central nervous system is much more complex and compartmentalized than it was thought.…”

Section: Alternative To Glucose Substrates For the Brain Energy Mementioning

confidence: 99%

“…A large scale utilization of glutamate by BM, as the energy-delivering substrate, is strongly suggested not only by the documented large scale transport of the mediator into neurons [ 80 , 124 ] but also by the properties of isolated BM and SCM [ 9 , 10 , 16 , 62 , 125 ]. In a number of recent works, we have shown that in the brain and spinal cord mitochondria, the major source of reactive oxygen species (ROS) production was associated with the reverse electron transport (RET) [ 10 , 125 ].…”

Section: Isolated Brain Mitochondria Have Strongly Inhibited Succmentioning

confidence: 99%

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Fatty Acids in Energy Metabolism of the Central Nervous System

Panov

Orynbayeva

Вавилин

et al. 2014

BioMed Research International

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162

144

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In this review, we analyze the current hypotheses regarding energy metabolism in the neurons and astroglia. Recently, it was shown that up to 20% of the total brain's energy is provided by mitochondrial oxidation of fatty acids. However, the existing hypotheses consider glucose, or its derivative lactate, as the only main energy substrate for the brain. Astroglia metabolically supports the neurons by providing lactate as a substrate for neuronal mitochondria. In addition, a significant amount of neuromediators, glutamate and GABA, is transported into neurons and also serves as substrates for mitochondria. Thus, neuronal mitochondria may simultaneously oxidize several substrates. Astrocytes have to replenish the pool of neuromediators by synthesis de novo, which requires large amounts of energy. In this review, we made an attempt to reconcile β-oxidation of fatty acids by astrocytic mitochondria with the existing hypothesis on regulation of aerobic glycolysis. We suggest that, under condition of neuronal excitation, both metabolic pathways may exist simultaneously. We provide experimental evidence that isolated neuronal mitochondria may oxidize palmitoyl carnitine in the presence of other mitochondrial substrates. We also suggest that variations in the brain mitochondrial metabolic phenotype may be associated with different mtDNA haplogroups.

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Section: Alternative To Glucose Substrates For the Brain Energy Mementioning

confidence: 99%

Section: Isolated Brain Mitochondria Have Strongly Inhibited Succmentioning

confidence: 99%

Fatty Acids in Energy Metabolism of the Central Nervous System

Panov

Orynbayeva

Вавилин

et al. 2014

BioMed Research International

Self Cite

162

144

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“…Studies of mitochondrial DNA (mtDNA) cytosine methylation and the Dnmts that regulate mtDNA methylation are not as common as studies of nuclear DNA methylation; moreover, many mitochondrial-based mechanisms of disease have been implicated in amyotrophic lateral sclerosis (ALS) (Beal, 2005 ; Martin, 2010 , 2012 ; Reddy and Reddy, 2011 ; Panov et al, 2012 ; Santa-Cruz et al, 2012 ), but mtDNA methylation and mitochondrial Dnmts have not been studied in ALS. Earlier work tends to minimize the occurrence and importance of mtDNA cytosine methylation.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS

Wong

Gertz

Chestnut

et al. 2013

Front. Cell. Neurosci.

152

144

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Cytosine methylation is an epigenetic modification of DNA catalyzed by DNA methyltransferases. Cytosine methylation of mitochondrial DNA (mtDNA) is believed to have relative underrepresentation; however, possible tissue and cell differences in mtDNA methylation and relationships to neurodegenerative disease have not been examined. We show by immunoblotting that DNA methyltransferase 3A (Dnmt3a) isoform is present in pure mitochondria of adult mouse CNS, skeletal muscle, and testes, and adult human cerebral cortex. Dnmt1 was not detected in adult mouse CNS or skeletal muscle mitochondria but appeared bound to the outer mitochondrial membrane. Immunofluorescence confirmed the mitochondrial localization of Dnmt3a and showed 5-methylcytosine (5mC) immunoreactivity in mitochondria of neurons and skeletal muscle myofibers. DNA pyrosequencing of two loci (D-loop and 16S rRNA gene) and twelve cytosine-phosphate-guanine (CpG) sites in mtDNA directly showed a tissue differential presence of 5mC. Because mitochondria have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but the disease mechanisms are uncertain, we evaluated mitochondrial Dnmt3a and 5mC levels in human superoxide dismutase-1 (SOD1) transgenic mouse models of ALS. Mitochondrial Dnmt3a protein levels were reduced significantly in skeletal muscle and spinal cord at presymptomatic or early disease. Immunofluorescence showed that 5mC immunoreactivity was present in mitochondria of neurons and skeletal myofibers, and 5mC immunoreactivity became aggregated in motor neurons of ALS mice. DNA pyrosequencing revealed significant abnormalities in 16S rRNA gene methylation in ALS mice. Immunofluorescence showed that 5mC immunoreactivity can be sequestered into autophagosomes and that mitophagy was increased and mitochondrial content was decreased in skeletal muscle in ALS mice. This study reveals a tissue-preferential mitochondrial localization of Dnmt3a and presence of cytosine methylation in mtDNA of nervous tissue and skeletal muscle and demonstrates that mtDNA methylation patterns and mitochondrial Dnmt3a levels are abnormal in skeletal muscle and spinal cord of presymptomatic ALS mice, and these abnormalities occur in parallel with loss of myofiber mitochondria.

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“…One notable feature of normal motor terminals is a dense supply of mitochondria (Yoshikami and Okun, 1984). Accumulating evidence indicates that mitochondrial dysfunction is a component of the disease process in SOD1 mice (Damiano et al, 2006; Panov et al, 2012; Pedrini et al, 2010; Santa-Cruz et al, 2012), including evidence for dysfunction at the motor terminal (David et al, 2007; Nguyen et al, 2011). The dense supply of mitochondria at motor terminals likely reflects the relatively large metabolic demands of maintaining ionic equilibrium in a small structure featuring a high surface to volume ratio.…”

Section: Introductionmentioning

confidence: 99%

Motor terminal degeneration unaffected by activity changes in SOD1G93A mice; a possible role for glycolysis

Carrasco

Bichler

Rich

et al. 2012

Neurobiology of Disease

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This study examined whether activity is a contributing factor to motor terminal degeneration in mice that overexpress the G93A mutation of the SOD1 enzyme found in humans with inherited motor neuron disease. Previously, we showed that overload of muscles accomplished by synergist denervation accelerated motor terminal degeneration in dogs with hereditary canine spinal muscular atrophy (HCSMA). In the present study, we found that SOD1 plantaris muscles overloaded for 2 months showed no differences of neuromuscular junction innervation status when compared with normally loaded, contralateral plantaris muscles. Complete elimination of motor terminal activity using blockade of sciatic nerve conduction with tetrodotoxin cuffs for 1 month also produced no change of plantaris innervation status. To assess possible effects of activity on motor terminal function, we examined the synaptic properties of SOD1 soleus neuromuscular junctions at a time when significant denervation of close synergists had occurred as a result of natural disease progression. When examined in glucose media, SOD1 soleus synaptic properties were similar to wildtype. When glycolysis was inhibited and ATP production limited to mitochondria, however, blocking of evoked synaptic transmission occurred and a large increase in the frequency of spontaneous mEPCs was observed. Similar effects were observed at neuromuscular junctions in muscle from dogs with inherited motor neuron disease (HCSMA), although significant defects of synaptic transmission exist at these neuromuscular junctions when examined in glucose media, as reported previously. These results suggest that glycolysis compensates for mitochondrial dysfunction at motor terminals of SOD1 mice and HCSMA dogs. This compensatory mechanism may help to support resting and activity-related metabolism in the presence of dysfunctional mitochondria and prolong the survival of SOD1 motor terminals.

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Role of Neuronal Mitochondrial Metabolic Phenotype in Pathogenesis of ALS

Cited by 5 publications

References 98 publications

Fatty Acids in Energy Metabolism of the Central Nervous System

Fatty Acids in Energy Metabolism of the Central Nervous System

Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS

Motor terminal degeneration unaffected by activity changes in SOD1G93A mice; a possible role for glycolysis

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